The disulfide bond as a chemical tool in cyclic peptide antibiotics: engineering disulfide polymyxins and murepavadin

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The increase of multidrug-resistant (MDR) pathogens has become a matter of global concern. It has been recently estimated that 4.95 million people died worldwide due to drug-resistant bacterial infections in 2019. Of those, 1.27 million deaths were directly attributed to antimicrobial resistance (AMR). In Europe, the European Centre for Disease Prevention and Control (ECDC) has reported that antibiotic-resistant bacterial infections caused 33,000 deaths (data for the European Economic Area). Similarly, in the US, the CDC estimates that more than 2.8 million antibiotic-resistant infections take place annually with more than 35,000 dead people as a consequence. The WHO and CDC have identified Gram-negative pathogens such as carbapenem-resistant strains of Acinetobacter baumannii, Enterobacteriaceae (which including Escherichia coli and Klebsiella pneumoniae), and Pseudomonas aeruginosa (also multi-drug resistant strains) as urgent or serious threats. Regarding the number of deaths associated with resistance, six leading pathogens (E. coli, S. aureus, K. pneumoniae, Streptococcus pneumoniae, A. baumannii, and P. aeruginosa) were responsible for ca 929,000 deaths attributable to AMR in 2019.In particular, colistin-resistant, carbapenem-resistant, or multidrug-resistant P. aeruginosa shows some of the highest impact related to deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European Economic Area in 2015. Hence, the treatment of these P. aeruginosa caused infections is a clear unmet medical need in the field. In this regards, antimicrobial peptides, particularly those that are cyclic, non-ribosomally biosynthesized (or ribosomally synthesized and post-translationally modified) offer an opportunity to be explored as potential drugs. In this class we find well-known clinically-used drugs such as daptomycin and polymyxins (polymyxin B and polymyxin E/colistin, used in the prodrug form colistimethate) or novel compounds such as darobactin or teixobactin. Daptomycin is mostly indicated to treat Gram-positive Staphylococcus aureus caused infections, whereas polymyxins have become a last resort therapeutic option to treat multi-drug resistant (MDR) Gram-negative bacteria (GNB) caused infections. Polymyxins are used as last resort antibiotics when no other therapeutic option is available due to their nephrotoxicity and neurotoxicity. Hence, the availability of novel polymyxins devoid of such adverse effects would be a great advance for the treatment of infections caused by multi-drug resistant (MDR) Gram-negative bacteria. The project presents an innovative chemical tool to be applied to known cyclic peptide antibiotics, including those in clinical use or in a clinical development phase, to reduce their nephrotoxicity. The rationale of the design consists of maintaining the overall structure of the antibiotic to preserve the antibacterial activity while the presence of the chemical tool within the peptide backbone would facilitate the initial metabolization by detoxifying enzymes upon eventual accumulation of the antibiotic in the kidney. The project follows a proof-of-concept scheme involving the necessary chemistry to prepare the model compounds, the in vitro and in vivo assays to assess activity and low toxicity, and estimation the therapeutic window. Finally, tests to prove the design hypothesis and the mechanism of action at the membrane level are also proposed.